阅读说明：本技术 一种达格列净新晶型及其制备方法 (Novel dapagliflozin crystal form and preparation method thereof ) 是由 葛书旺 唐伟 杨文谦 王铁林 于 2019-02-13 设计创作，主要内容包括：本发明涉及一种达格列净新晶型及其制备方法。具体而言,本发明的达格列净新晶型的使用Cu-Kα测量的X射线粉末衍射图谱在以下2θ角处具有特征衍射峰：5.347±0.2°,7.623±0.2°,10.484±0.2°,15.308±0.2°,15.850±0.2°。本发明的晶型的含水量低、纯度高、产品稳定性高、晶癖好。(The invention relates to a novel dapagliflozin crystal form and a preparation method thereof. Specifically, the X-ray powder diffraction pattern of the novel crystalline form of dapagliflozin of the present invention measured using Cu-K α has characteristic diffraction peaks at the following 2 θ angles: 5.347 + -0.2 deg., 7.623 + -0.2 deg., 10.484 + -0.2 deg., 15.308 + -0.2 deg., 15.850 + -0.2 deg.. The crystal form of the invention has low water content, high purity, high product stability and good crystal habit.)

1. A crystalline form of dapagliflozin having characteristic diffraction peaks at the following 2 Θ angles using an X-ray powder diffraction pattern measured at Cu-ka: 5.347 + -0.2 deg., 7.623 + -0.2 deg., 10.484 + -0.2 deg., 15.308 + -0.2 deg., 15.850 + -0.2 deg..

2. The crystalline form of dapagliflozin of claim 1, having an X-ray powder diffraction pattern measured using Cu-ka with characteristic diffraction peaks at six or more, seven or more, eight or more, nine or more, ten or more, or eleven or more 2 Θ angles selected from the group of: 5.347 +/-0.2 degrees, 7.623 +/-0.2 degrees, 8.143 +/-0.2 degrees, 9.446 +/-0.2 degrees, 10.484 +/-0.2 degrees, 15.308 +/-0.2 degrees, 15.850 +/-0.2 degrees, 17.416 +/-0.2 degrees, 20.122 +/-0.2 degrees, 24.601 +/-0.2 degrees, 29.612 +/-0.2 degrees and 30.398 +/-0.2 degrees.

3. The crystalline form of dapagliflozin of claim 2, having an X-ray powder diffraction pattern as shown in figure 1 of the accompanying drawings measured using Cu-ka.

4. The crystalline form of dapagliflozin of claim 1, having an endothermic peak at 53.89 ± 3 ℃ in a differential scanning calorimetry curve.

5. The crystalline form of dapagliflozin of claim 4, having a differential scanning calorimetry curve as shown in figure 2 of the accompanying drawings.

6. The crystalline dapagliflozin form of claim 1, having a thermogravimetric analysis curve with a weight loss of about 0.943% at 150 ± 3 ℃.

7. The crystalline form of dapagliflozin of claim 6, having the thermogravimetric analysis curve shown in figure 3 of the accompanying drawings.

8. A method of preparing a crystalline form of dapagliflozin, the method comprising: 1) dissolving amorphous dapagliflozin in water; 2) filtering with a filter membrane, standing the filtrate at low temperature for crystallization; and 3) carrying out suction filtration and reduced pressure drying.

9. Use of the crystalline form of dapagliflozin of any one of claims 1-7 or prepared by the method of claim 8 in the preparation of a medicament for the treatment of type 2 diabetes.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a novel dapagliflozin crystal form and a preparation method thereof.

Background

Dapagliflozin is a commonly used medicament for treating diabetes clinically. The mechanism of action is to inhibit the sodium-glucose co-transporter 2(SGLT2) which reabsorbs glucose from the urine, thereby increasing urinary glucose excretion. On the basis of diet and exercise, dapagliflozin can be used as a monotherapy for type 2 diabetes patients to improve glycemic control.

The original research crystal form patent (CN20078024135.X) reports 10 co-crystals including (S) propylene glycol monohydrate, (R) propylene glycol monohydrate, ethanolate, ethanol dihydrate, ethylene glycol dihydrate (A), ethylene glycol dihydrate (B), L-proline (1:2) compound, L-proline (1:1) hemihydrate, and L-phenylalanine (1:1) compound. The original research does not obtain a non-aqueous crystal form of dapagliflozin, but adopts propylene glycol monohydrate eutectic, which indicates that the difficulty in developing the non-aqueous dapagliflozin crystal form is higher, and simultaneously the use of propylene glycol needs to be overcome, and a new dapagliflozin crystal form needs to be developed.

Disclosure of Invention

The invention provides a dapagliflozin crystal form which has characteristic diffraction peaks at the following 2theta angles by using an X-ray powder diffraction pattern measured by Cu-Ka: 5.347 + -0.2 deg., 7.623 + -0.2 deg., 10.484 + -0.2 deg., 15.308 + -0.2 deg., 15.850 + -0.2 deg..

In one embodiment, the crystalline form has an X-ray powder diffraction pattern measured using Cu-ka having characteristic diffraction peaks at six or more, seven or more, eight or more, nine or more, ten or more, or eleven or more 2 Θ angles selected from the group consisting of: 5.347 +/-0.2 degrees, 7.623 +/-0.2 degrees, 8.143 +/-0.2 degrees, 9.446 +/-0.2 degrees, 10.484 +/-0.2 degrees, 15.308 +/-0.2 degrees, 15.850 +/-0.2 degrees, 17.416 +/-0.2 degrees, 20.122 +/-0.2 degrees, 24.601 +/-0.2 degrees, 29.612 +/-0.2 degrees and 30.398 +/-0.2 degrees.

In another embodiment, the crystalline form has an X-ray powder diffraction pattern, as measured using Cu-ka, as shown in figure 1.

In another embodiment, the crystalline form has X-ray powder diffraction pattern analysis data measured using Cu-ka as shown in table 1.

TABLE 1X-ray powder diffraction Pattern analysis data for dapagliflozin crystalline forms of the invention measured using Cu-Ka

In another embodiment, the crystalline form has a differential scanning calorimetry curve with an endothermic peak at 53.89 ± 3 ℃.

In another embodiment, the crystalline form has a differential scanning calorimetry curve as shown in figure 2.

In another embodiment, the crystalline form has a thermogravimetric analysis curve with a weight loss of about 0.943% at 150 ± 3 ℃.

In another embodiment, the thermogravimetric analysis curve of the crystalline form is shown in figure 3.

In another embodiment, the present invention also discloses a method of preparing a crystalline form of dapagliflozin, the method comprising: 1) dissolving amorphous dapagliflozin in water; 2) filtering with a filter membrane, standing the filtrate at low temperature for crystallization; and 3) carrying out suction filtration and reduced pressure drying.

The invention also provides application of the dapagliflozin crystal form in preparation of medicines for treating type 2 diabetes.

Drawings

Figure 1 shows an X-ray powder diffraction pattern of a crystalline form of dapagliflozin of the present invention.

Fig. 2 shows a differential scanning calorimetry curve for the dapagliflozin crystalline form of the invention.

Fig. 3 shows a thermogravimetric analysis curve of the crystalline form of dapagliflozin of the present invention.

Fig. 4 shows the crystal habit of the dapagliflozin crystalline form of the invention.

Detailed Description

The invention is further described below with reference to the figures and examples. It should be understood, however, that these examples are for the purpose of illustrating the invention in more detail, and are not to be construed as limiting the invention in any way.

The reagents and methods employed in the examples of the invention are conventional in the art. It will be clear to those skilled in the art that, unless otherwise specified, temperatures are expressed in degrees Celsius (C.) and operating temperatures are carried out at ambient temperature, which is 10 deg.C to 30 deg.C, preferably 20 deg.C to 25 deg.C; the allowable error of the melting point is +/-1%; the yield is mass percent.

Experimental methods

X-ray powder diffraction (XRPD)

XRPD data for the crystalline form was determined by brueck (d8advance) with the following diffraction parameters:

x-ray:

x-ray light pipe setting: 40kV and 25mA

Divergent slit: automatic

A monochromator: is free of

Scanning mode: continuous

Scan range (° 2 Theta): 4-40 degree

Scanning speed (sec/step): 0.5

2. Differential Scanning Calorimetry (DSC)

The DSC data of the crystalline form are determined by a differential scanning calorimeter of type TA (DSC 25) with the following thermal analysis parameters:

temperature range (. degree. C.): 30-300

Scanning rate (. degree. C./min): 10

Protective gas: nitrogen gas

3. Thermogravimetric analysis (TGA)

TGA data for the crystalline form was determined by a TA (TGA 550) instrument with the following thermal analysis parameters:

temperature range (. degree. C.): 30-350 deg.C

Scanning rate (. degree. C./min): 10

Protective gas: nitrogen gas

5. High Performance Liquid Chromatography (HPLC) detection

The conditions for HPLC detection were as follows:

technical effects

The crystal form of the invention has low water content, high purity, high product stability and good crystal habit.